SUBSTITUTION OF THE HUMAN BETA-SPECTRIN PROMOTER FOR THE HUMAN (A)GAMMA-GLOBIN PROMOTER PREVENTS SILENCING OF A LINKED HUMAN BETA-GLOBIN GENE IN TRANSGENIC MICE

During development, changes occur in both the sites of erythropoiesis and the globin genes expressed at each developmental stage. Previous w ork has shown that high-level expression of human beta-like globin gen es in transgenic mice requires the presence of the locus control regio n (LCR), Models of hemoglobin switching propose that the LCR and/or st age-specific elements interact with globin gene sequences to activate specific genes in erythroid cells. To test these models, we generated transgenic mice which contain the human (A)gamma-globin gene linked to a 576-bp fragment containing the human beta-spectrin promoter. In the se mice, the beta-spectrin (A)gamma-globin (beta sp/(A)gamma) transgen e was expressed at high levels in erythroid cells throughout developme nt. Transgenic mice containing a 40-kb cosmid construct with the micro LCR, beta sp/(A)gamma-, psi beta-, delta-, and beta-globin genes show ed no developmental switching and expressed both human gamma- and beta -globin mRNAs in erythroid cells throughout development. Mice containi ng control cosmids with the (A)gamma-globin gene promoter showed devel opmental switching and expressed (A)gamma-globin mRNA in yolk sac and fetal liver erythroid cells and beta-globin mRNA in fetal liver and ad ult erythroid cells. Our results suggest that replacement of the gamma -globin promoter with the beta-spectrin promoter allows the expression of the beta-globin gene. We conclude that the gamma-globin promoter i s necessary and sufficient to suppress the expression of the beta-glob in gene in yolk sac erythroid cells.